DESCRIPTION: Alzheimer's disease is a devastating and common disease of the central nervous system, and studies of familial forms have identified a number of loci that are implicated in the development of the disease. The C. elegans model that is the subject of this proposal is based on the finding that the sel-12 gene encodes a protein that is highly similar to two genes associated with early-onset familial Alzheimer's disease. The remarkable conservation of the predicted C. elegans and human proteins suggests that their functions are likely to be conserved as well. Furthermore, nearly all mutations associated with early-onset familial Alzheimer's disease in people alter amino acids that are identical in SEL-12. The Principal Investigator hopes to bring the tools of classical and molecular genetic studies in C. elegans to bear on fundamental issues of the structure and function of SEL-12 and its human homologs. The specific aims of this proposal are: I.A basic characterization of sel-12. The proposed experiments will directly test the functional equivalence of S182, STM2 and SEL-12. Other experiments are concerned with establishing the null phenotype, characterizing the expression pattern, identifying behavioral defects, generating antibodies to SEL-12, and identifying C. elegans genes that are highly similar to sel-12. II. To engineer sel-12 transgenes ["sel-12(Alz)"] containing alterations associated with early-onset familial Alzheimer's disease. The proposed experiments are concerned with the generation and genetic and phenotypic analyses of sel-12(Alz) transgenic lines. III. The identification and characterization of extragenic suppressors of sel-12(ar171) and sel-12(Alz). The proposed experiments are concerned with the reversion of sel-12(ar171) and sel-12(Alz) mutants, and genetic and molecular analyses of suppressor genes.